Francis A. Bainbridge demonstrated in 1915 that an infusion of saline or blood into the jugular vein of the anesthetized dog produced tachycardia. His findings after transection of the cardiac autonomic nerve supply and injection of the cholinergic blocking drug atropine demonstrated that the tachycardia was reflex in origin, with the vagus nerves constituting the afferent limb and a withdrawal of vagal tone the primary efferent limb. Subsequent investigators demonstrated that the increase in venous return was detected by stretch receptors in the right and left atria. In the 1980s, it was shown convincingly that the Bainbridge reflex was present in primates, including humans, but that the reflex was much less prominent than in the dog. This difference may be due to a more dominant arterial baroreceptor reflex in humans. A “reverse” Bainbridge reflex has been proposed to explain the decreases in heart rate observed under conditions in which venous return is reduced, such as during spinal and epidural anesthesia, controlled hypotension, and severe hemorrhage. The Bainbridge reflex is invoked throughout the anesthesia literature to describe the effect of changes in venous return on heart rate in patients in the surgical and critical care settings, but a critical analysis of the experimental and clinical evidence is lacking. Our main objectives in this review are to summarize the history of the Bainbridge reflex, to describe its anatomy and physiology, and to discuss the evidence for and against it having an influence on heart rate changes observed clinically. The interaction of the Bainbridge reflex with the arterial baroreceptor and Bezold–Jarisch reflexes is discussed.